Arginine-vasopressin (AVP) is a peptide composed of nine amino acids, which is synthesized mainly in the hypothalamus, and as a posterior pituitary hormone it is closely related to the regulation of plasma osmotic pressure, blood pressure, and body fluid level.
Three sub-types of AVP receptor, namely, V1a, V1b, and V2 receptors, have been cloned, and all are known to be “seven transmembrane receptors”. The V2 receptor couples with Gs and increases the cAMP level. The V1a receptor couples with Gq/11, promotes PI response, increases intracellular Ca, is expressed in the brain, liver, adrenal gland, vascular smooth muscle, and so on, and is involved in vascular contraction. Meanwhile, the V1b receptor is similar to the V1a receptor in that it couples with Gq/11 and promotes PI response (Non-Patent Documents 1 and 2). The V1b receptor is most prevalent in the pituitary gland (expressed in over 90% of ACTH-secreting cells of the anterior lobe), and has been presumed to be involved in ACTH secretion from the anferior lobe of pituitary by AVP. In addition to being found in the pituitary, the V1b receptor is also found over a wide region of the brain, and is also prevalent in the raphe nuclei, which are the nuclei of serotonergic neurons, the cerebral cortex, and the olfactory bulb, and parts of the limbic system such as the hippocampus, amygdala, and entorhinal cortex (Non-Patent Documents 3 and 4).
Relationship between the V1b receptor and depression and anxiety disorders has recently been suggested, and the usefulness of a V1b receptor antagonist has been studied. It has been indicated that aggressive behavior is reduced in V1b receptor KO mice (Non-Patent Document 5). It has also been reported that injection of a V1b receptor antagonist into the septum prolongs the time on open-arms in an elevated plus maze test (anxiolytic action) (Non-Patent Document 6). More recently, a V1b receptor-specific antagonist has been synthesized that is a systemically administrable 1,3-dihydro-2H-indol-2-one derivative (Non-Patent Documents 1 to 6). Also, 1,3-dihydro-2H-indol-2-one derivatives have been reported exhibit antidepressant and anxiolytic effects in various animal models (Non-Patent Documents 7 and 8). The compound disclosed in Patent Document 1 exhibits high affinity (1 to 4×10−9 mol/L) and selectivity towards a V1b receptor, and is antagonistic to AVP, AVP+CRF, and restraint stress-induced ACTH increase.
However, Patent Documents 1 to 6 do not disclose a compound which a fluorine atom has been introduced into a pyrrolidine ring bonded to the 3-position of 1,3-dihydro-2H-indol-2-one.
Non-Patent Document 1: Sugimoto T., Kawashima G, J. Biol. Chem., 269, 27088-27092, 1994.
Non-Patent Document 2: Lolait S., Brownstein M., PNAS, 92, 6783-6787, 1995.
Non-Patent Document 3: Vaccari C., Ostrowski N., Endocrinology, 139, 5015-5033, 1998.
Non-Patent Document 4: Hernando F., Burbach J., Endocrinology, 142, 1659-1668, 2001.
Non-Patent Document 5: Wersinger S. R., Toung W. S., Mol. Psychiatry, 7, 975-984, 2002.
Non-Patent Document 6: Liebsch G., Engelmann M., Neurosci. Lett., 217, 101-104, 1996.
Non-Patent Document 7: Gal C. S., Le Fur G., 300, 1122-1130, 2002.
Non-Patent Document 8: Griebel G., Soubrie P., 99, 6370a-6375, 2002.
Patent Document 1: WO01/55130 pamphlet
Patent Document 2: WO01/55134 pamphlet
Patent Document 3: WO01/64668 pamphlet
Patent Document 4: WO01/98295 pamphlet
Patent Document 5: WO03/008407 pamphlet
Patent Document 6: WO2004/009585 pamphlet